Dauricine alleviates cognitive impairment in Alzheimer's disease mice induced by D-galactose and AlCl via the Ca/CaM pathway.

Alzheimer's disease (AD) is a common neurodegenerative disease in the elderly. Dysregulation of intracellular Ca homeostasis plays a critical role in the pathological development of AD. Dauricine (DAU) is a bisbenzylisoquinoline alkaloid isolated from Menispermum dauricum DC., which can prevent the influx of extracellular Ca and inhibit the release of Ca from the endoplasmic reticulum. DAU has a potential for anti-AD. However, it is unclear whether DAU can exert its anti-AD effect in vivo by regulating the Ca related signaling pathways. Here, we investigated the effect and mechanism of DAU on D-galactose and AlCl combined-induced AD mice based on the Ca/CaM pathway. The results showed that DAU (1 mg/kg and 10 mg/kg for 30 days) treatment attenuated learning and memory deficits and improved the nesting ability of AD mice. The HE staining assay showed that DAU could inhibit the histopathological alterations and attenuate neuronal damage in the hippocampus and cortex of AD mice. Studies on the mechanism indicated that DAU decreased the phosphorylation of CaMKII and Tau and reduced the formation of NFTs in the hippocampus and cortex. DAU treatment also reduced the abnormally high expression of APP, BACE1, and Aβ, which inhibited the deposition of Aβ plaques. Moreover, DAU could decrease Ca levels and inhibit elevated CaM protein expression in the hippocampus and cortex of AD mice. The molecular docking results showed that DAU may have a high affinity with CaM or BACE1. DAU has a beneficial impact on pathological changes in AD mice induced by D-galactose and AlCl and may act by negative regulation of the Ca/CaM pathway and its downstream molecules such as CaMKII and BACE1.